Field of the Invention
This application is in the field of medicinal chemistry. The application relates to a novel process for preparing 7β-substituted 6α,14α-ethenomorphinans and 7β-substituted 6α,14α-ethanomorphinans, and the pharmaceutically acceptable salts thereof. Particularly, the application relates to the selective precipitation of 7β-substituted 6α,14α-ethenomorphinans or 7β-substituted 6α,14α-ethanomorphinans from a mixture containing corresponding 7α-epimers by treating with an acid. Contrary to optical diastereomeric resolution of enantiomers (e.g., chiral bases) which requires chiral acids to resolve single enantiomers, the separation of the above-mentioned 7α/7β-epimers can be achieved even with achiral acids. The application also relates to the novel, isolated compounds and salts thereof.
Description of the Related Art
6α,14α-Ethenomorphinans and 6α,14α-ethanomorphinans are semi-synthetic oripavine or thebaine derivatives. The central structural element of this class of molecules is a morphinan ring system with an etheno or ethano bridge between the C-6 and C-14 carbons of the morphinan scaffold. Based on the nature of the carbon-carbon-bond between C-18 and C-19, these compounds are classified as 6α,14α-ethenomorphinans (carbon-carbon-double bond) or 6β,14α-ethanomorphinans (saturated carbon-carbon bond). The morphinan scaffold has the following structure:

6α,14α-Ethenomorphinan derivatives with a substituent in the 7-position have been extensively studied over the last 60 years. During this time, drugs like Buprenorphine (Temgesic®, Subutex®, Suboxone®), Diprenorphine (Revivon®) and Etorphine (Immobilon®) were discovered. Buprenorphine is commercially the most important representative of this class of compounds and has been on the market since 1978 as a powerful analgesic and for the management of opioid dependence.
Buprenorphine, (2S)-2-[17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14α-ethanomorphinan-7α-yl]-3,3-dimethylbutan-2-ol, a semi-synthetic opioid having the structure:
is used to treat opioid addiction, to control moderate acute pain in non-opioid tolerant individuals, and to control moderate chronic pain. Buprenorphine can be derived from either oripavine or thebaine: K. W. Bentley discovered buprenorphine using thebaine as the initial backbone structure. Thebaine is one of the main alkaloids in the Iranian poppy (Papaver bracteatum). Thebaine can also be isolated from Papaver somniferum which is also a source for oripavine (U.S. Pat. No. 6,723,894).
Buprenorphine has an extremely high binding affinity at the μ- and κ-opioid receptors. It has partial agonist activity at the μ-opioid receptor, partial or full agonist activity at the ORL-1/nociception and δ-opioid receptors, and competitive antagonist activity at the κ-opioid receptor. Buprenorphine exhibits an analgesic effect approximately 25 to 40 times more potent than morphine (by weight of equivalent low doses). Buprenorphine is marketed as oral formulations (tablets, sublingual tablets, and sublingual films), parenteral preparations, and transdermal patches.
All the above-mentioned drugs within this class of compounds contain an alkyl substituent attached to the nitrogen and a hydroxyl group attached to a lipophilic substituent in 7α-position of the C-ring. Through comparison of a large number of derivatives, it has become clear that the region above and away from C-7 has a significant impact on the μ-opioid receptor profile of these orvinols and related compounds (Hutchins et al., J. Med. Chem. 27:521-527 (1984); Coop et al., J. Med. Chem. 43:1852-1857 (2000).
This 7α-configuration (e.g. 7α-substituted 6α,14α-ethenomorphinan), found in all commercial drugs of this class of compounds, is however not a structural requirement for opioid receptor affinity, but rather a result of limited accessibility of the 7β-substituted derivatives (e.g. 7β-substituted 6α,14α-ethenomorphinan). The structures of 7α-6α,14α-ethenomorphinans/ethanomorphinans and 7β-6α,14α-ethenomorphinans/ethanomorphinans are shown in Figure 1 below: